What makes non-cirrhotic portal hypertension a common disease in India? Analysis for environmental factors.

In India, an unexplained enteropathy is present in a majority of non-cirrhotic intrahepatic portal hypertension (NCIPH) patients. Small intestinal bacterial contamination and tropical enteropathy could trigger inflammatory stimuli and activate the endothelium in the portal venous system. Groundwater contaminated with arsenic is an environmental factor of epidemic proportions in large areas of India which has similar consequences. Von Willebrand factor (a sticky protein) expressed by activated endothelium may promote formation of platelet microthrombi and occlusion of intrahepatic portal vein branches leading to NCIPH. Environmental factors linked to suboptimal hygiene and sanitation, which enter through the gastrointestinal (GI) tract, predispose to platelet plugging onto activated endothelium in portal microcirculation. Thus, NCIPH, an example of poverty linked thrombophilia, is a disease mainly affecting the lower socio-economic strata of Indian population. Public health measures to improve sanitation, provide clean drinking water and eliminate arsenic contamination of drinking water are urgently needed. Till such time as these environmental factors are addressed, NCIPH is likely to remain 'an Indian disease'.

Raised plasma levels of H2S and nitrate predict intrapulmonary vascular dilations: A preliminary report in patients with cryptogenic cirrhosis.

BACKGROUND AND AIMS: The role of vasoactive chemicals in the pathogenesis of hepatopulmonary syndrome (HPS), a disorder characterized by intrapulmonary vascular dilation (IPVD), is only vaguely elucidated. We aimed to study the association between plasma H2S, nitrate levels, and presence and severity of IPVD and HPS. METHODS: Consecutive adult patients with cryptogenic cirrhosis were evaluated for IPVD (by contrast echocardiography) and for hypoxemia (by arterial blood gas analysis). Plasma H2S and nitrate levels were measured in these patients. RESULTS: Fifty-eight patients with cryptogenic cirrhosis (male, 45; median age, range, 45, 16-74 years; Child's class; A, 30; B, 18; C, 10) were enrolled in this study. Thirty-four of the 58 (59%) patients had IPVD and 13 (22%) had HPS (mild, 4; moderate, 5; severe, 2; very severe, 2). Plasma H2S levels were significantly higher in patients with IPVD (19.6, 5.7-83 µmol/L) as compared to patients who had no IPVD (12.3, 0-47 µmol/L; p-value 0.03) with an area under receiver operating characteristic curve of 0.68 (95% CI 0.53-0.84). Plasma H2S levels were higher in patients with IPVD irrespective of liver disease severity. There was a trend for higher plasma nitrate levels in patients with IPVD (47, 15.8-126.4 nmol/mL) as compared to patients who had no IPVD (32.3, 6.9-51.4 nmol/mL; p-value 0.1). Raised plasma H2S and nitrate levels had an additive effect on the presence of IPVD. Neither plasma H2S nor plasma nitrate levels correlated with the degree of hypoxemia. CONCLUSION: Raised plasma H2S and nitrate levels predict the presence of IPVD in patients with cryptogenic cirrhosis.

Plasma von Willebrand factor levels predict in-hospital survival in patients with acute-on-chronic liver failure.

BACKGROUND AND AIMS: Circulating levels of von Willebrand factor (vWF) predict mortality in patients with cirrhosis. We hypothesized that systemic inflammation in acute-on-chronic liver failure (ACLF) will stimulate endothelium, increase vWF levels, and promote platelet microthrombi causing organ failure. METHODS: In this prospective study, we correlated plasma vWF levels with organ failure, liver disease severity, sepsis, and systemic inflammatory response syndrome (SIRS) and also analyzed if vWF levels predicted in-hospital composite poor outcome (i.e. death/discharged in terminal condition/liver transplantation) in consecutive ACLF patients. RESULTS: Twenty-one of the 50 ACLF patients studied had composite poor outcome. ACLF patients had markedly elevated vWF antigen and activity (sevenfold and fivefold median increase, respectively) on days 1 and 3. Median ratio of vWF to a disintegrin and metalloprotease with thrombospondin type 1 motif, member 13 (ADAMTS13) activity on day 1 was significantly higher in ACLF patients (11.2) compared to 20 compensated cirrhosis patients (3.3) and healthy volunteers (0.9). On day 1, area under ROC curve (AUROC) to predict composite poor outcome of hospital stay for ACLF patients for vWF antigen, vWF activity, and model for end-stage liver disease (MELD) score were 0.63, 0.68, and 0.74, respectively. vWF activity correlated better with liver disease severity (MELD score, ACLF grade) and organ failure (Sequential Organ Failure Assessment [SOFA] score) than vWF antigen; in contrast, neither vWF antigen nor activity correlated with platelet count, sepsis, or SIRS. CONCLUSIONS: vWF levels are markedly elevated, correlate with organ failure, and predict in-hospital survival in ACLF patients. This data provides a mechanistic basis for postulating that vWF-reducing treatments such as plasma exchange may benefit ACLF patients.

Clinicopathological profile and management of severe autoimmune hepatitis.

BACKGROUND: Severe autoimmune hepatitis is an entity which has been rarely reported in the Indian literature. We describe here the clinicopathological profile and treatment of severe autoimmune hepatitis (SAH) which is to the best of our knowledge the first report from India addressing this illness. METHODS AND RESULTS: Between September 2010 and March 2013, 13 patients seeking treatment at our centre were diagnosed as SAH and treated with steroids. Jaundice along with coagulopathy was the presenting symptom in all these patients. Ascites was present in ten and encephalopathy in 6 patients. The median serum IgG was 2135 mg/dl (range: 1122-5490).Significant titers of autoantibodies were present in all patients except one. Transjugular liver biopsy in 9 patients showed characteristic features of SAH such as extensive bridging necrosis and moderate to dense portal inflammation. With corticosteroid therapy, 10 patients survived while three died. In those who survived, biochemical improvement was seen as early as seven days with excellent long-term remission. CONCLUSIONS: Clinical suspicion supported by liver biopsy and autoimmune serology led to the diagnosis of SAH in a cohort of patients with unexplained liver failure. Corticosteroids were beneficial in majority of patients affording excellent results and this could be predicted by early reduction in serum bilirubin within 7-15 days.

Serum cholinesterase is an excellent biomarker of liver cirrhosis.

BACKGROUND: Serum cholinesterase (ChE) is an enzyme synthesised by hepatocytes and its serum levels reflect the synthetic function of liver. METHODS: In patients with cirrhosis, liver function tests, PT INR and serum ChE levels were done within a week of enrolment. We studied 178 cirrhosis patients and 154 healthy controls prospectively. Receiver operator characteristics (ROC) curve analysis was employed to compute an optimal cut-off level to distinguish these groups. Correlation between ChE activity and serum bilirubin, albumin, PT INR and MELD score (Model for End-Stage Liver Disease) was analysed. RESULTS: Median serum ChE in cirrhotics was 1590 IU/L (110-8143) compared to controls 7886 IU/L (2022- 21673), p < 0.001. Serum ChE levels below 3506 had a 98.7% sensitivity and 80.3% specificity in predicting cirrhosis. Median serum ChE was higher (p < 0.001) in CC (n = 51) 4246 IU/L (680-8143) compared to DC (n = 127) 1324 IU/L (110-4550). ChE level less than 2385 IU/L had 80.1% sensitivity and 88.2% specificity in predicting DC. Follow-up levels in 25 patients showed good correlation with clinical course. The correlation coefficient between ChE and albumin was -0.67, 0.53 with PT INR and 0.59 with MELD score, (p < 0.001). CONCLUSIONS: Serum ChE is an excellent biomarker of cirrhosis with good sensitivity and specificity. It shows good correlation with serum albumin, PT INR and MELD score. Since it distinguishes DC from CC well, low levels in cirrhosis may serve as a useful prognostic marker of advanced liver disease. Long-term follow-up studies are warranted to define its exact role in clinical practice.

A study of aetiology of portal hypertension in adults (including the elderly) at a tertiary centre in southern India.

BACKGROUND & OBJECTIVES: There are only a few studies on aetiology of portal hypertension among adults presenting to tertiary care centres in India; hence we conducted this study to assess the aetiological reasons for portal hypertension in adult patients attending a tertiary care centre in southern India. METHODS: Causes of portal hypertension were studied in consecutive new adult patients with portal hypertension attending department of Hepatatology at a tertiary care centre in south India during July 2009 to July 2010. RESULTS: A total of 583 adult patients (>18 yr old) were enrolled in the study. After non-invasive testing, commonest causes of portal hypertension were cryptogenic chronic liver disease (35%), chronic liver disease due to alcohol (29%), hepatitis B (17%) or hepatitis C (9%). Of the 203 patients with cryptogenic chronic liver disease, 39 had liver biopsy - amongst the latter, idiopathic non cirrhotic intrahepatic portal hypertension (NCIPH) was seen in 16 patients (41%), while five patients had cirrhosis due to non alcoholic fatty liver disease. Fifty six (10%) adult patients with portal hypertension had vascular liver disorders. Predominant causes of portal hypertension in elderly (>60 yrs; n=83) were cryptogenic chronic liver disease (54%) and alcohol related chronic liver disease (16%). INTERPRETATION & CONCLUSIONS: Cryptogenic chronic liver disease was the commonest cause of portal hypertension in adults, followed by alcohol or hepatitis B related chronic liver disease. Of patients with cryptogenic chronic liver disease who had liver biopsy, NCIPH was the commonest cause identified. Vascular liver disorders caused portal hypertension in 10 per cent of adult patients. Cryptogenic chronic liver disease was also the commonest cause in elderly patients.

Hepatocellular carcinoma continues to be diagnosed in the advanced stage: profile of hepatocellular carcinoma in a tertiary care hospital in South India.

This report is an analysis of 231 patients with hepatocellular carcinoma (HCC) from a tertiary care hospital in India. Most of the HCCs were diagnosed in cirrhotics and at an advanced stage which limited the therapeutic options. Physician awareness of this complication of cirrhosis and regular ultrasound screening of cirrhotic patients will help in detection of early stage cancers and, thus, enhance the survival rates.

Use of serum vitamin B12 level as a marker to differentiate idiopathic noncirrhotic intrahepatic portal hypertension from cryptogenic cirrhosis.

BACKGROUND AND AIMS: Idiopathic non-cirrhotic intrahepatic portal hypertension (NCIPH) is often mis-diagnosed as cryptogenic cirrhosis. Serum vitamin B12 levels can be raised in cirrhosis, probably because of excess release or reduced clearance. Because NCIPH is characterised by long periods of preserved liver function, we examined whether serum B12 level could be used as a marker to differentiate NCIPH from cryptogenic cirrhosis. METHODS: We analysed serum B12 levels in 45 NCIPH and 43 cryptogenic cirrhosis patients from January 2009 to September 2011. RESULTS: Serum B12 levels were significantly lower in NCIPH patients than in cryptogenic cirrhosis patients (p < 0.001) and were useful in differentiating the two disorders (area under ROC: 0.84; 95% C.I: 0.76-0.93). Low serum B12 level (≤250 pg/ml) was noted in 25/72 (35%) healthy controls, 14/42 (33%) NCIPH patients, and 1/38 (3 %) cryptogenic cirrhosis patients. In patients with intrahepatic portal hypertension of unknown cause, serum B12 level ≤ 250 pg/ml was useful for diagnosing NCIPH (positive predictive value: 93 %, positive likelihood ratio 12.7), and serum B12 level >1,000 pg/ml was useful in ruling out NCIPH (negative predictive value: 86 %, negative likelihood ratio: 6.67). Low serum B12 levels (≤250 pg/ml) correlated with diagnosis of NCIPH after adjusting for possible confounders (O.R: 13.6; 95% C.I:1.5-126.2). Among patients in Child's class A, serum B12 level was ≤250 pg/ml in 14/35 NCIPH patients compared with 1/21 cryptogenic cirrhosis patients (O.R: 13.3; 95% C.I: 1.6-111). CONCLUSION: Serum vitamin B12 level seems to be a useful non-invasive marker for differentiation of NCIPH from cryptogenic cirrhosis.

Recurrent acute pancreatitis: clinical profile and an approach to diagnosis.

BACKGROUND AND AIMS: Though recurrent acute pancreatitis is often seen in clinical practice, there are few comprehensive articles on this entity. The aim of this study therefore was to assess the etiological and clinical profile as well as diagnostic yield of non-invasive and invasive tests in this group of patients. METHODS: All patients with recurrent acute pancreatitis seen from 2002 to 2007 were included in the study, retrospectively. Clinical information, investigation, and treatment data were collected for all patients by a standardized review of medical charts. Diagnostic tests were grouped into level one (non-invasive) and level two (invasive) tests and their yield was assessed. Comparison was made between the group with known etiology and idiopathic group to look for significant differences. RESULTS: A total of 188 patients with recurrent acute pancreatitis were seen during the study period. Common etiological factors were biliary disease (37%), pancreas divisum (8.5%) and alcohol (6.4%). Multiple etiologies were seen in 7% of cases, and no cause was found in 32.4%. The diagnostic yield of level-one investigation (non-invasive) was 29.3%. Level-two tests (invasive) identified presumptive etiologies in 38.3% of cases. Complications developed in 12.2% and there was no mortality. Clinical features and complications were similar in the idiopathic group and those with known etiology. CONCLUSIONS: Etiological diagnosis was obtained in 67.6% of patients after comprehensive diagnostic work up. Diagnosis in the majority of patients could only be reached after invasive tests (bile crystal analysis, EUS, ERCP). Early diagnosis and etiology-based therapy is the key to optimum patient outcome.